Gene Therapy Strategies for the Treatment of Bestrophinopathies

Journal article : Review

The BEST1 gene encodes a transmembrane protein in the retinal pigment epithelium (RPE) in the eye, that functions as a calcium-dependent chloride channel (CaCC). Pathogenic variants in BEST1 are the underlying cause for bestrophinopathies, a group of inherited retinal disorders that vary in their pattern of inheritance, clinical appearance, and underlying molecular disease mechanisms. Currently, there are no treatments available for any of the bestrophinopathies, and gene therapy represents an attractive strategy due to the accessibility of the eye and slow disease progression. While gene augmentation may be effective for a subset of bestrophinopathies, others require allele-specific silencing or correction of the disease-causing variant to reconstitute expression of the BEST1 protein. This review aims to give an overview of the clinical diversity of bestrophinopathies and proposes the molecular disease mechanism of the pathogenic BEST1 variant as an important parameter for the choice of treatment strategy. Furthermore, we discuss the potential of different mutation-specific and mutation-independent CRISPR/Cas9-based gene editing strategies as a future treatment approach for bestrophinopathies.

Authors: Haldrup, SB; McClements, ME; Cehajic-Kapetanovic, J; Corydon, TJ; MacLaren, RE

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: MDPI
• Journal: International Journal of Molecular Sciences
• Volume: 26
• Issue: 19
• Article number: 9421
• Publication date: 2025-09-26
• Acceptance date: 2025-08-29
• DOI: 10.3390/ijms26199421
• EISSN: 1422-0067
• ISSN: 1661-6596
• Language: English
• Keywords: gene therapy; CRISPR; bestrophinopathies; gene editing; BEST1
• Subtype: Review